Sharon E. Maynard

Angiogenic factors and preeclampsia.

Preeclampsia, a hypertensive disorder peculiar to pregnancy, is a systemic syndrome that appears to originate in the placenta and is characterized by widespread maternal endothelial dysfunction. Until recently, the molecular pathogenesis of phenotypic preeclampsia was largely unknown, but recent observations support the hypothesis that altered expression of placental anti-angiogenic factors are responsible for the clinical manifestations of the disease. Soluble Flt1 and soluble endoglin, secreted by the placenta, are increased in the maternal circulation weeks before the onset of preeclampsia. These anti-angiogenic factors produce systemic endothelial dysfunction, resulting in hypertension, proteinuria, and the other systemic manifestations of preeclampsia. The molecular basis for placental dysregulation of these pathogenic factors remains unknown, and as of 2011 the role of angiogenic proteins in early placental vascular development was starting to be explored. The data linking angiogenic factors to preeclampsia have exciting clinical implications, and likely will transform the detection and treatment of preeclampsia.

Soluble Fms-like Tyrosine Kinase 1 and Endothelial Dysfunction in the Pathogenesis of Preeclampsia

Preeclampsia, a pregnancy-specific syndrome of hypertension and proteinuria, is characterized by defective placental vasculogenesis and widespread maternal endothelial dysfunction. Although the manifestations of preeclampsia are primarily maternal, the burden of morbidity and mortality is often on the neonate, since the only effective treatment—delivery of the fetus and placenta—often results in iatrogenic prematurity. In this review, we summarize recent advances in our understanding of the pathophysiology of preeclampsia, including normal and aberrant placental vascular development and evidence for endothelial dysfunction. We describe recent evidence that supports a novel mechanism in which a maladaptive shift in placental production of angiogenic factors such as soluble fms-like tyrosine kinase 1 (a circulating antiangiogenic protein) may play an important role in the pathogenesis of preeclampsia.

Pregnancy and the Kidney

Nephrologists are frequently called on to diagnose and treat renal disorders in pregnant women. In this review, we update recent literature pertinent to pregnancy and renal disease. We initially begin by describing the application of common clinical estimators of GFR and proteinuria in pregnancy and then summarize recent studies regarding pregnancy in women with chronic kidney disease and the latest information on the use of common renal medications in pregnancy. In the final section, we describe advances in our understanding of the pathophysiology of preeclampsia and the potential clinical implications of these discoveries for screening, prevention, and treatment of preeclampsia.

Angiogenic biomarkers for prediction of maternal and neonatal complications in suspected preeclampsia

Objective: To determine if maternal serum angiogenic factors predict maternal and neonatal complications in women presenting to an acute care setting with suspected preeclampsia. Study design: Maternal serum samples were prospectively collected from women with suspected preeclampsia at the time of initial presentation to hospital triage with signs or symptoms of preeclampsia. Soluble fms-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF), and soluble endoglin (sEng) were measured by ELISA. The primary outcome was a composite of maternal and neonatal complications. Results: Of 276 women with suspected preeclampsia, 78 developed maternal or neonatal complications. Among women presenting prior to 37 weeks gestation, sFlt1, PlGF, and sEng were significantly different in women who developed maternal and neonatal complications as compared to women without complications. Higher levels of sFlt1, sEng, and the sFlt1:PlGF ratio were associated with an increased odds of complications among women presenting prior to 37 weeks. A multivariable model combining the sFlt1:PlGF ratio with clinical variables was more predictive of complications (AUC 0.91, 95% CI 0.85–0.97) than a model using clinical variables alone (AUC 0.82, 95% CI 0.79–0.90). Conclusion: Angiogenic biomarkers associate with maternal and neonatal complications in women with suspected preeclampsia, and may be useful for risk stratification.

Misapplications of Commonly Used Kidney Equations: Renal Physiology in Practice

Equations for estimating GFR, quantifying urinary protein excretion, and assessing renal sodium handling are widely used in routine nephrology and general medical and surgical practice. If these equations are applied in circumstances inconsistent with the clinical situations for or extrapolated beyond the limits in which they were validated, clinicians can come to erroneous conclusions, which could be detrimental for patient care. This review uses clinical vignettes to demonstrate some of the common pitfalls that clinicians may encounter in the use of these equations and considers the physiologic principles underlying their use. Equations for assessing aspects of renal function should only be used in specific clinical situations, if the underlying assumptions regarding their calculations and values are satisfied.

Angiogenic biomarkers for prediction of early preeclampsia onset in high-risk women

Abstract Objective: Chronic hypertension, pregestational diabetes mellitus, history of prior preeclampsia and obese nulliparity are maternal conditions associated with increased preeclampsia risk. Whether altered maternal angiogenic factor levels allow for prediction of pending disease is unclear. Our objective was to evaluate angiogenic factors for early preeclampsia prediction in high-risk women. Methods: Serial serum specimens were collected from 157 women at high preeclampsia risk and 50 low-risk controls between 23 and 36 weeks gestation in 3 windows (23–27.6, 28–31.6, and 32–35.6 weeks) in a two-center observational cohort. Soluble fms-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF) and soluble endoglin (sEng) were measured by ELISA. Results: Multivariate parsimonious logistic regression analyses using backward elimination for prediction of early-preeclampsia (diagnosed < 34 weeks) found the best-fitting model included the predictors (1) sFlt1 measured in the second window (28–31.6 weeks) with AUC 0.85, sensitivity 67% and specificity 96% and (2) sFlt1 measured in the first window (23–27.6 weeks) and sEng change between first and second window with AUC 0.91, sensitivity 86% and specificity 96%. Conclusions: Two-stage sampling screening protocol utilizing sFlt1 and sEng is promising for prediction of preeclampsia diagnosed before 34 weeks. Larger studies are needed to confirm these findings.

Soluble Endoglin for the Prediction of Preeclampsia in a High Risk Cohort

Objectives. To evaluate soluble endoglin (sEng) and the soluble fms-like tyrosine kinase 1 (sFlt1) to placental growth factor (PlGF) ratio for the prediction of preeclampsia in high-risk women, and to evaluate differences in sEng between women with high-risk singleton and multiple gestation pregnancies. Study Design. We collected serial serum specimens from 119 women at high preeclampsia risk. sEng, sFlt1 and PlGF were measured by ELISA. Results. Among subjects who did not develop preeclampsia, mean serum sEng was significantly higher in those with multiple gestation pregnancies vs. high-risk singletons. Among women with singleton gestations, mean serum sEng was higher in subjects who developed early-onset (<34 weeks) and late-onset (≥ 34 weeks) preeclampsia, as compared with subjects without preeclampsia, from 22 weeks and 28 weeks gestation onward, respectively. The within-woman rate of change of sEng was also higher in women who later developed preeclampsia. Conclusions. sEng is higher in women with multiple gestations vs. high-risk singleton pregnancies. In high-risk women, serum sEng is increased prior to preeclampsia onset.

Association of cotinine levels and preeclampsia among African-American women.

INTRODUCTION Although prior studies have shown that smoking reduces preeclampsia risk, the relationship between nicotine level and preeclampsia risk is not known. Our objective was to study the effects of smoking on the incidence of preeclampsia in African-American women using cotinine, a quantitative marker of nicotine. METHODS We performed a secondary analysis of data collected prospectively in Project District of Columbia Healthy Outcomes of Pregnancy Education. Our study included 724 African-American women. Self-reported smoking, cotinine levels, and pregnancy outcomes were examined. RESULTS Some 18% of participants were smokers. Women with salivary cotinine levels greater than 200 ng/ml had infants with lower birth weights and a higher incidence of small-for-gestational-age infants than women with cotinine levels of 200 ng/ml or less. Exact logistic regression analysis revealed that women with salivary cotinine levels greater than 200 ng/ml had a significantly lower incidence of preeclampsia, compared with women with cotinine levels of 200 ng/ml or less, in unadjusted analysis (odds ratio [OR] = 0.16, 95% CI = 0-0.90). After controlling for age, parity, and medical comorbidities, the trend was observed, but the effect was no longer significant (adjusted odds ratio [AOR] = 0.19, 95% CI = 0-1.11). We found no significant differences in preeclampsia rates using lower cutoffs of cotinine exposure. We did not observe a decrease in preeclampsia incidence at low or moderate cotinine levels. DISCUSSION Women with the highest cotinine levels may have a decreased risk for preeclampsia, although this effect was not significant after controlling for other risk factors.

Circulating Levels of sFlt1 Splice Variants as Predictive Markers for the Development of Preeclampsia

Angiogenic biomarkers, including soluble fms-like tyrosine kinase 1 (sFlt1), are thought to be predictors of preeclampsia onset; however, improvement is needed before a widespread diagnostic test can be utilized. Here we describe the development and use of diagnostic monoclonal antibodies specific to the two main splice variants of sFlt1, sFlt1-1 and sFlt1-14. These antibodies were selected for their sensitivity and specificity to their respective sFlt1 isoform in a capture ELISA format. Data from this pilot study suggest that sFlt1-1 may be more predictive of preeclampsia than total sFlt1. It may be possible to improve current diagnostic platforms if more specific antibodies are utilized.

Career interest and perceptions of nephrology: A repeated cross-sectional survey of internal medicine residents

Background Interest in nephrology careers among internal medicine residents in the United States is declining. Our objective was to assess the impact of the presence of a nephrology fellowship training program on perceptions and career interest in nephrology among internal medicine residents. A secondary objective was to identify commonly endorsed negative perceptions of nephrology among internal medicine residents. Methods This was a repeated cross-sectional survey of internal medicine residents before (Group 1) and 3 years after (Group 2) the establishment of nephrology fellowship programs at two institutions. The primary outcome was the percentage of residents indicating nephrology as a career interest in Group 1 vs. Group 2. Secondary outcomes included the frequency that residents agreed with negative statements about nephrology. Results 131 (80.9%) of 162 residents completed the survey. 19 (14.8%) residents indicated interest in a nephrology career, with 8 (6.3%) indicating nephrology as their first choice. There was no difference in career interest in nephrology between residents who were exposed to nephrology fellows during residency training (Group 2) and residents who were not (Group 1). The most commonly endorsed negative perceptions of nephrology were: nephrology fellows have long hours/burdensome call (36 [28.1%] of residents agreed or strongly agreed), practicing nephrologists must take frequent/difficult call (35 [27.6%] agreed or strongly agreed), and nephrology has few opportunities for procedures (35 [27.3%] agreed or strongly agreed). More residents in Group 2 agreed that nephrology is poorly paid (8.9% in Group 1 vs. 20.8% in Group 2, P = 0.04), whereas more residents in Group 1 agreed that nephrologists must take frequent/difficult call (40.0% in Group 1 vs. 18.1% in Group 2, P = 0.02). Conclusions The initiation of a nephrology fellowship program was not associated with an increase in internal medicine residents’ interest in nephrology careers. Residents endorsed several negative perceptions of nephrology, which may affect career choice.